rs761189541
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_017802.4(DNAAF5):c.1997C>T(p.Ala666Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000342 in 1,461,130 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A666T) has been classified as Uncertain significance.
Frequency
Consequence
NM_017802.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DNAAF5 | NM_017802.4 | c.1997C>T | p.Ala666Val | missense_variant | 10/13 | ENST00000297440.11 | |
DNAAF5 | XM_024446813.2 | c.1997C>T | p.Ala666Val | missense_variant | 10/12 | ||
DNAAF5 | NR_075098.2 | n.1957C>T | non_coding_transcript_exon_variant | 10/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DNAAF5 | ENST00000297440.11 | c.1997C>T | p.Ala666Val | missense_variant | 10/13 | 1 | NM_017802.4 | P1 | |
DNAAF5 | ENST00000403952.3 | c.272C>T | p.Ala91Val | missense_variant | 3/6 | 1 | |||
DNAAF5 | ENST00000440747.5 | c.1403C>T | p.Ala468Val | missense_variant | 10/13 | 2 |
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 exomes AF: 0.00000800 AC: 2AN: 249854Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135254
GnomAD4 exome AF: 0.00000342 AC: 5AN: 1461130Hom.: 0 Cov.: 38 AF XY: 0.00 AC XY: 0AN XY: 726914
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Primary ciliary dyskinesia 18 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Feb 16, 2022 | - - |
Primary ciliary dyskinesia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2017 | In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies. This variant is present in population databases (rs761189541, ExAC 0.009%) but has not been reported in the literature in individuals with a DNAAF5-related disease. This sequence change replaces alanine with valine at codon 666 of the DNAAF5 protein (p.Ala666Val). The alanine residue is highly conserved and there is a small physicochemical difference between alanine and valine. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at